Interferons are antiviral glycoproteins produced by various mammalian cells in response to viruses and a wide variety of non-viral agents. The recent successful use of interferon in the treatments of viral diseases in man and tumors in animals has stimulated an interest among therapists which rivals the excitement generated when antibiotics were first introduced. However, interferon is known to affect living cells in many ways. In 1976 we made the unexpected observation that a great variety of interferon inducing agents cause a marked depression of cytochrome P-450-mediated drug metabolism in rats and mice. The hepatic P-450 system largely determines the intensity and duration of drug action because it metabolizes most drugs to less toxic, readily excreted products. Thus a depressed P-450 system can result in exaggerated drug effects (toxicity). Since patients who receive interferon will frequently be treated with other drugs, it will be important to know to what extent interferon or interferon inducing agents depress drug metabolism in man. The current proposal is an attempt to answer the question of whether the depression of P-450 is due to interferon per se or to a process involving the induction of interferon. Our direct approach will be to determine the effects of purified interferon on the P-450 systems of cultured hepatocytes, continuously perfused livers and intact animals. However, the failure of exogenous interferon to produce an effect on P-450 systems does not exclude the possibility that endogenous interferon induced by viruses and other agents may produce the effect. Indirect studies using interferon inducing agents are therefore proposed. These studies take advantage of temporal differences in the induction of interferon by different agents, of quantitative and qualitative differences in the induction produced by these agents, of strain differences in the response of mice to the agents, and of the hyporeactivity of mice to inducing agents. Other studies are designed to assess the extent of the reciprocal relationship between P-450 and interferon systems. In addition, the ability of interferon inducing agents to destroy individual species of P-450 selectively will be investigated. Clinical studies are also proposed which will determine what effect human interferon and the interferon inducing agent, poly rI.rC lysine complex, may have on drug metabolism in man.